1. Field of the Invention
The present invention relates to certain sufonamide derivatives that inhibit procollagen C-proteinase, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
2. Background Information and Related Disclosures
The collagens are integral components of connective tissue. At present nineteen types of collagens have been identified. The interstitial collagen types I, II, and III are the major collagen components of tissue. These collagens are synthesized as procollagen precursor molecules having amino- and carboxy-terminal peptide extensions also known as pro-regions. These pro-regions are typically cleaved upon secretion of the procollagen molecule to give a mature collagen molecule which is capable of association into highly structured collagen fibers, ((see, e.g., Fessler and Fessler, Annu. Rev. Biochem. 47, 129, (1978); Kivirikko et al., Extracellular Matrix Biochemistry (1984) and Kuhn, Structure and Function of Collagen Types (eds. Mayne, R and Burgeson, R. E.), Academic Press, Inc., Orlando, Fla., pp. 1-42 (1987)). It is well established that excessive collagen deposition is associated with a variety of fibrotic diseases such as interstitial pulmonary fibrosis, pericentral fibrosis, Symmers"" fibrosis, perimuscular fibrosis, kidney fibrosis, endocardial sclerosis, hepatitis, acute respiratory distress syndrome, arthritis, cystic fibrosis, tendon surgery, corneal scarring, surgical adhesions, scleroderma, chronic allograft rejection, hemodialysis shunt fibrosis, liver fibrosis and restenosis. These diseases are chatacterized by excessive deposits of fibrillar interstitial collagens that are resistant to proteolytic degradation thus leading to the symptoms of fibrosis. Therefore, inhibition of the pathological deposition of these collagens should help in the treatment of these diseases.
Recent studies suggest that C-proteinase is the essential enzyme that catalyzes the cleavage of the C-propeptide of types I, II, and III collagens and is therefore instrumental in the formation of functional collagen fibers ((see, Fertala et al., J. Biol. Chem., 269, 11584, (1994)). It would therefore be desirable to provide procollagen C-proteinase inhibitors and thereby provide a means of combating diseases mediated by excessive deposition of these collagens. The compounds of this invention fulfill this and related needs.
In a first aspect, this invention provides sulfonamide derivatives selected from the group of compounds represented by Formula (I): 
wherein:
Z is xe2x80x94OH, xe2x80x94NHOH, or OR12 wherein R12 is alkyl;
R1 is alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)-C(O)xe2x80x94X where X is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy, cycloalkylalkoxy, heteroalkyloxy, aralkyloxy, or heteroaralkyloxy), or xe2x80x94C(xe2x95x90NRxe2x80x2)NHSO2Rxe2x80x3 (where Rxe2x80x2 is hydrogen or alkyl, and Rxe2x80x3 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclylalkyl);
R is xe2x80x94CH(R2)Ar1 or xe2x80x94CH(R2)CHxe2x95x90CHAr1 where R2 is hydrogen or alkyl; and Ar1 is aryl or heteroaryl;
Ar2 is either:
(i) a phenyl ring of formula (a): 
xe2x80x83wherein:
R3 and R7 are, independently of each other, hydrogen, alkyl, alkylthio, or halo;
R4 and R6 are, independently of each other, hydrogen, alkyl, or halo;
R5 is alkyl, haloalkyl, heterocyclyl, alkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, cycloalkylthio, cycloalkylalkylthio, alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyloxy, cycloalkoxy, cycloalkylalkoxy, alkyloxycarbonyl, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl, heteroaralkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, or xe2x80x94Y-(alkylene)-C(O)xe2x80x94Z [where Y is a bond, xe2x80x94NRaxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94S(O)nxe2x80x94 (where n is 0 to 2), Ra is hydrogen or alkyl, and Z is alkoxy, hydroxy, amino, monosubstituted amino, or disubstituted amino]; or
R5 together with R4 forms xe2x80x94Oxe2x80x94 (CR8R9)nxe2x80x94 where n is 2 or 3 and each R8 and R9 are, independently of each other, hydrogen or alkyl; or
the carbon atoms to which R5 and R4 are attached are fused to the C2-C3 carbons of a benzofuran ring; provided that at least two of R3, R4, R6, and R7 are not hydrogen at the same time; or
(ii) a naphthyl ring of formula (b): 
xe2x80x83wherein:
R10 is hydrogen, alkyl, alkoxy, or halo; and
R11 is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino or alkylsulfonyl
provided that both R10 and R11 are not hydrogen at the same time; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers.
Within the group of compounds represented by Formula (I), sulfonamide derivatives of this invention wherein Z is NHOH are represented by Formula (Ia): 
In a second aspect, this invention provides a method of treatment of a disease treatable by administration of a therapeutically effective amount of a procollagen C-proteinase inhibitor of Formula (Ib) wherein: 
wherein:
R1 is alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)-C(O)xe2x80x94X (where X is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy, cycloalkylalkoxy, heteroalkyloxy, aralkyloxy, or heteroaralkyloxy), or xe2x80x94C(xe2x95x90NRxe2x80x2)NHSO2Rxe2x80x3 (where Rxe2x80x2 is hydrogen or alkyl, and Rxe2x80x3 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclylalkyl);
R is xe2x80x94CH(R2)Ar1 or xe2x80x94CH(R2)CHxe2x95x90CHAr1 where R2 is hydrogen or alkyl; and Ar1 is aryl or heteroaryl;
Ar2 is either:
(i) a phenyl ring of formula (a): 
xe2x80x83wherein:
R3 and R7 are, independently of each other, hydrogen, alkyl, alkylthio, or halo;
R4 and R6 are, independently of each other, hydrogen, alkyl, or halo;
R5 is alkyl, haloalkyl, heterocyclyl, alkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, cycloalkylthio, cycloalkylalkylthio, alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyloxy, cycloalkoxy, cycloalkylalkoxy, alkyloxycarbonyl, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl, heteroaralkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, or xe2x80x94Y-(alkylene)-C(O)xe2x80x94Z [where Y is a bond, xe2x80x94NRaxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94S(O)nxe2x80x94(where n is 0 to 2), Ra is hydrogen or alkyl, and Z is alkoxy, hydroxy, amino, monosubstituted amino, or disubstituted amino]; or
R5 together with R4 forms xe2x80x94Oxe2x80x94 (CR8R9)nxe2x80x94 where n is 2 or 3 and each R8 and R9 are, independently of each other, hydrogen or alkyl; or
the carbon atoms to which R5 and R4 are attached are fused to the C2-C3 carbons of a benzofuran ring; or
(ii) a naphthyl ring of formula (b): 
xe2x80x83wherein:
R10 is hydrogen, alkyl, alkoxy, or halo; and
R11 is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino or alkylsulfonyl; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers.
In a third aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (Ia) or (Ib) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a fourth aspect, this invention provides a process for preparing compounds of Formula (Ia) or (Ib).
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, n-propyl, 2-propyl, tert-butyl, pentyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
xe2x80x9cAlkenylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monovalent cyclic hydrocarbon radical of three to seven ring carbons. The cycloalkyl may be optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano, optionally substituted phenyl, optionally substituted heteroaralkyl, xe2x80x94OR (where R is hydrogen, alkyl, or haloalkyl, xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently hydrogen or alkyl), or xe2x80x94C(O)R (where R is hydrogen, alkyl, or optionally substituted phenyl). More specifically, the term cycloalkyl includes, for example, cyclopropyl, cyclohexyl, 1,2-dihydroxycyclopropyl, and the like.
xe2x80x9cMonosubstituted aminoxe2x80x9d means a radical xe2x80x94NHR where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, or heterocyclylalkyl, e.g., methylamino, ethylamino, phenylamine, benzylamine, dibenzylamine, and the like.
xe2x80x9cDisubstituted aminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are, independently of each other, is alkyl, haloalkyl, cyanoalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclyl, or heterocyclylalkyl, or R and Rxe2x80x2 together with the nitrogen atom to which they are attached form a heterocyclyl ring. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di(1-methyl-ethyl)amino, piperazinyl, and the like.
xe2x80x9cMonoalkylaminoxe2x80x9d means a radical xe2x80x94NHR where R is alkyl, e.g., methylamino, ethylamino, and the like.
xe2x80x9cDialkylaminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are independently of each other alkyl. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di(1-methylethyl)amino, and the like.
xe2x80x9cArylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms which is substituted independently with one or more substituents, preferably one, two, or three substituents selected from alkyl, haloalkyl, thioalkyl, heteroalkyl, halo, nitro, cyano, optionally substituted phenyl, heteroaryl, heterocyclyl, hydroxy, alkoxy, haloalkoxy, optionally substituted phenyloxy, heteroaryloxy, methylenedioxy, ethylenedioxy, xe2x80x94COR (where R is alkyl or optionally substituted phenyl), -(alkylene)nxe2x80x94COOR (where n is 0 or 1 and R is hydrogen, alkyl, optionally substituted phenylalkyl, or heteroaralkyl), xe2x80x94NRaRb (where Ra and Rb are independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, optionally substituted phenyl, or heteroaryl), xe2x80x94NRaCORb (where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl, haloalkyl, or optionally substituted phenyl), xe2x80x94S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or heteroaryl], xe2x80x94SO2NRaRb (where Ra and Rb are, independently of each other hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl, or Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclyl ring), xe2x80x94NRSO2Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or heteroaryl), xe2x80x94NRSO2NRxe2x80x2Rxe2x80x3 (where R is hydrogen or alkyl and Rxe2x80x2 and Rxe2x80x3 are, independently of each other, hydrogen, alkyl, or hydroxyalkyl, or Rxe2x80x2 and Rxe2x80x3 together with the nitrogen atom to which they are attached form a heterocyclyl ring), or -(alkylene)nxe2x80x94CONRaRb (where n is 0 or 1, and Ra and Rb are, independently of each other, hydrogen or alkyl, or Ra and Rb together with the nitrogen atom to which they are attached form a heterocyclyl ring). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, and 2-naphthyl, and the derivatives thereof.
xe2x80x9cOptionally substituted phenylxe2x80x9d means a phenyl ring which is optionally substituted independently with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, thioalkyl, hydroxyalkyl, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, amino, methylenedioxy, ethylenedioxy, xe2x80x94COR (where R is alkyl), xe2x80x94COOR (where R is alkyl), xe2x80x94NRaRb (where Ra and Rb are independently of each other hydrogen or alkyl), xe2x80x94NRaCORb (where Ra is hydrogen or alkyl and Rb is alkyl, haloalkyl, or optionally substituted phenyl), or xe2x80x94CONRaRb (where Ra and Rb are independently of each other hydrogen or alkyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-napthyl, and 2-naphthyl, and the derivatives thereof.
xe2x80x9cHeteroarylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic radical of 5 to 12 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. The heteroaryl ring is optionally substituted independently with one or more substituents, preferably one or two substituents, selected from alkyl, haloalkyl, heteroalkyl, heterocyclyl, halo, nitro, cyano, xe2x80x94OR (where R is hydrogen, alkyl, haloalkyl, optionally substituted phenyl, or optionally substituted heteroaryl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are, independently of each other, hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, or optionally substituted phenyl), xe2x80x94C(O)R (where R is hydrogen, alkyl, or optionally substituted phenyl), -(alkylene)nxe2x80x94COOR (where n is 0 or 1 and R is hydrogen, alkyl, optionally substituted phenylalkyl, or optionally substituted heteroaralkyl),xe2x80x94S(O)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted heteroaryl], xe2x80x94SO2NRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are, independently of each other, hydrogen, alkyl, hydroxyalkyl, or optionally substituted phenyl, or Rxe2x80x2 and Rxe2x80x3 together with the nitrogen atom to which they are attached form a heterocyclyl ring), xe2x80x94NRC(O)Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, haloalkyl, or optionally substituted phenyl), xe2x80x94NRSO2Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, or optionally substituted heteroaryl), xe2x80x94NRSO2NRxe2x80x2Rxe2x80x3 (where R is hydrogen or alkyl, and Rxe2x80x2 and Rxe2x80x3 are, independently of each other, hydrogen or alkyl, or Rxe2x80x2 and Rxe2x80x3 together with the nitrogen atom to which they are attached form a heterocyclyl ring), -(alkylene)nxe2x80x94CONRxe2x80x2Rxe2x80x3 (where n is 0 or 1 and Rxe2x80x2 and Rxe2x80x3 are, independently of each other, hydrogen or alkyl, or Rxe2x80x2 and Rxe2x80x3 together with the nitrogen atom to which they are attached form a heterocyclyl ring), or an amino protecting group. More specifically the term heteroaryl includes, but is not limited to, pyridyl, furanyl, thiophenyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, indolyl, isoindolyl, benzoxazolyl, quinolyl, isoquinolyl, benzimidazolyl, benzisoxazolyl, benzothiophenyl, dibenzofuran, and benzodiazepin-2-one-5-yl, and the derivatives thereof.
xe2x80x9cHeterocyclylxe2x80x9d means a saturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyl group. The heterocyclo ring may be optionally substituted independently with one, two, or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted phenyalkyl, optionally substituted heteroaralkyl, xe2x80x94OR (where R is hydrogen, alkyl, or haloalkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently hydrogen or alkyl), xe2x80x94C(O)R (where R is hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, or aryloxyalkyl), xe2x80x94COOR (where R is hydrogen, alkyl, aryl, aralkyl, heteroaralkyl), -(alkylene)-COOR (where R is hydrogen, alkyl, optionally substituted phenyl, optionally substituted phenyalkyl, or optionally substituted heteroaralkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3, or -(alkylene)-COONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl), xe2x80x94S(O)nR (where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0) or alkyl), alkoxycarbonyl, xe2x80x94NRC(O)Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is hydrogen or alkyl), xe2x80x94NRSO2Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl), xe2x80x94NRSO2NRxe2x80x2Rxe2x80x3 (where R, Rxe2x80x2 and Rxe2x80x3 are independently hydrogen or alkyl), or an amino protecting group. The heterocyclo ring also may be optionally fused with an aryl ring as defined above. More specifically the term heterocyclo includes, but is not limited to, tetrahydropyranyl, piperidino, piperazino, morpholino and thiomorpholino, thiomorpholino-1-oxide, thiomorpholino-1,1-dioxide, and the derivatives thereof.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl, cycloalkyl, or cycloalkylalkyl radical as defined above, carrying a substituent selected from xe2x80x94NRaRb, xe2x80x94ORc, or xe2x80x94S(O)nRd wherein n is an integer from 0 to 2, Ra is hydrogen, alkyl, or xe2x80x94COR (where R is hydrogen, alkyl, or haloalkyl); Rb is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclyhydroxyalkyl, xe2x80x94COR (where R is hydrogen, alkyl, haloalkyl, monosubstituted aminoalkyl, aryloxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, or -(alkylene)-C(O)xe2x80x94X (where X is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, or heterocyclyalkyl), xe2x80x94SO2R (where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, amino, monosubstituted amino or disubstituted amino), xe2x80x94COOR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclylalkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3, or -(alkylene)-CONRxe2x80x2Rxe2x80x3 [where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or SO2R (where R is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, amino, monosubstituted amino or disubstituted amino), or Rxe2x80x2 and Rxe2x80x3 together with the nitrogen atom to which they are attached form a heterocyclyl ring]; Rc is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, xe2x80x94COR (where R is alkyl, haloalkyl, or heterocyclyl), or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl); and Rd is hydrogen (provided that n is 0), alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, amino, monosubstituted amino, or disubstituted amino. Representative examples include, but are not limited to hydroxymethyl, 2-hydroxyethyl, 2-methoxyethyl, benzyloxymethyl, thiophen-2-ylthiomethyl, and the like;
xe2x80x9cAralkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is an aryl group as defined above e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
xe2x80x9cAralkenylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkenyl group and Rb is an aryl group as defined above e.g., 3-phenyl-2-propenyl, and the like.
xe2x80x9cHeteroaralkylxe2x80x9d means a radical xe2x80x94Ra Rb where Ra is an alkylene group and Rb is a heteroaryl group as defined above e.g., pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
xe2x80x9cHeteroaralkenylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkenyl group and Rb is a heteroaryl group as defined above e.g., 3-pyridin-3-ylpropen-2-yl, and the like.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a heterocyclyl group as defined above e.g., tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl, 2-, or 3-piperidinylmethyl, and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d means a radical xe2x80x94RaRb where Ra is an alkylene group and Rb is a cycloalkyl group as defined above e.g., cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9caralkyloxyxe2x80x9d, or xe2x80x9cheteroaralkyloxyxe2x80x9d means a radical xe2x80x94OR where R is an alkyl, aryl, aralkyl, or heteroaralkyl respectively, as defined above e.g., methoxy, phenoxy, pyridin-2-ylmethyloxy, benzyloxy, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means an alkyl radical as defined above, carrying one or more, preferably one, two or three hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9cheterocyclo group optionally mono- or disubstituted with an alkyl groupxe2x80x9d means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
xe2x80x9cAmino protecting groupxe2x80x9d refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, 2-trimethylsilyl-ethanesulfonyl (SES), and the like.
Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed xe2x80x9cisomersxe2x80x9d. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and those that are non-superimposable mirror images of each other are termed xe2x80x9cenantiomersxe2x80x9d. When a compound has an asymmetric center, for example, where a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequence rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (xe2x88x92)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a xe2x80x9cracemic mixturexe2x80x9d.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition J. March, John Wiley and Sons, New York, 1992).
A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of formula (I) are prepared by modifying functional groups present in the compound of formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of formula (I), and the like.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The naming and numbering of the compounds of this invention is illustrated below. 
The nomenclature used in this application is generally based on the IUPAC recommendations, e.g., a compound of formula (Ia):
where R1 is xe2x80x94CH(CH3)2, R is xe2x80x94CH(R2)Ar1 wherein R2 is hydrogen, Ar1 is 3,4-methylenedioxyphenyl, Ar2 is 4-methoxyphenyl and the stereochemistry at the carbon to which R1 is attached is (R) is named, N-hydroxy-2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxybenzenesulfonyl)amino]-3-methylbutyramide.
where R1 is xe2x80x94CH2OH, R is xe2x80x94CH(R2)Ar1 wherein R2 is hydrogen, Ar1 is indol-5-yl, Ar2 is 2,3,6-trimethyl-4-methoxyphenyl and the stereochemistry at the carbon to which R1 is attached is (R) is named, N-hydroxy-2(R)-[(1H-indol-5-ylmethyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-hydroxypropionamide.
Representative compounds of this invention are as follows:
I. Compounds of Formula (Ia) and (Ib) wherein R is xe2x80x94CH(R2)Ar1 and the other groups are defined as follows:
II. Compounds of the Formula (Ia) and (Ib) wherein R is xe2x80x94CH(R2)Ar1, Ar2 is 2,3,6 trimethyl-4-methoxyphenyl or 2,6-dimethyl-4-methoxyphenyl, R2 is hydrogen, and the other groups are defined as follows:
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (Ia) wherein Z is NHOH are preferred. 
In addition, compounds of Formula (Ia) where Ar2 is at least tetra or penta-substituted are surprisingly selective in inhibiting procollagen C-proteinase relative to other collagenases.
I. A preferred group of compounds is that wherein:
R is xe2x80x94CH(R2)Ar1 wherein R2 is hydrogen.
(a) Within this preferred group (I) a more preferred group of compounds of that wherein:
Ar1 is heteroaryl and Ar2 is a phenyl ring of formula (a).
(i) Within this more preferred group (I)(a), an even more preferred group of compounds is that wherein:
R3 and R7 are, independently of each other, alkyl, alkylthio, or halo;
R4 is hydrogen, alkyl, or halo;
R5 is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, or alkylsulfonyl; and
R6 is hydrogen.
Within these preferred, more preferred and even more preferred groups of compounds, a particularly preferred group of compounds is that wherein:
Ar1 is a heteroaryl ring, preferably optionally substituted indolyl or imidazolyl, more preferably indol-5-yl, 1-methylindol-5-yl, 3-acetylindol-5-yl, 3-propionylindol-5-yl, 3-(2-methylpropionyl)indol-5-yl, imidazol-5-yl, 2-methylbenzimidazol-5-yl, or benzimidazol-5-yl;
R3 and R7 are, independently of each other, alkyl or halo, more preferably methyl, chloro, or bromo;
R4 is hydrogen or alkyl, preferably methyl; and
R5 is alkyl, alkoxy, or halo, preferably methyl, methoxy, chloro, or bromo.
Within these preferred, more preferred, and particularly preferred groups of compounds, an even more particularly preferred group of compounds is that wherein:
R1 is alkyl, aralkyl, heteroalkyl, or -(alkylene)-C(O)xe2x80x94X where X is alkyl, amino, monosubstituted amino, disubstituted amino, or heterocyclyl,
more preferably 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl, or -(alkylene-C(O)xe2x80x94X where X is 2- or 4-pyridylmethylamino, 1-alkoxycarbonylpyridin-4-ylamino, optionally substituted benzylamino, 4-optionally substituted benzyloxycarbonylpiperazin-1-yl, 4-optionally substituted phenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or 4-optionally substituted heteroarylpiperazin-1-yl,
most preferably 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl, 2-(2- or 4-pyridylmethylamino-carbonyl)ethyl, 2-(1-ethoxycarbonylpyridin-4-ylaminocarbonyl)-ethyl, 2-(benzylaminocarbonyl)ethyl, 2-(4-benzyloxycarbonylpiperizin-1-ylcarbonyl)-ethyl, 2-(4-phenylpiperazin-1-ylcarbonyl)-ethyl, 2-(4-methoxycarbonylpiperazin-1-ylcarbonyl)ethyl, 2-(4-acetylpiperazin-1-yl-carbonyl)ethyl, or 2-(4-pyridin-2-ylpiperazin-1-ylcarbonyl)ethyl.
Within these preferred, more preferred, and particularly preferred groups of compounds, an alternative even more particularly preferred group of compounds is that wherein:
R1 is heteroalkyl or -(alkylene)-C(O)xe2x80x94X where X is alkyl, amino, monosubstituted amino, disubstituted amino, or heterocyclyl,
more preferably, methylsulfonylaminomethyl, phenylsulfonylaminomethyl, (3-nitrophenyl)CH2SO2NHCH2, methylcarbonylaminomethyl, 4-(methoxycarbonyl)phenylcarbonylaminomethyl, 2-(pyrrol-1-yl)phenylcarbonylaminomethyl, 3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl, phenylcarbonylaminomethyl, (C6H5)CHCH3NHCO(C2H4)CONHCH2, (4-methoxyphenyl)COC2H4CONHCH2, 4-chlorophenylsulfonylaminocarbonylaminomethyl, 5-(acetyl)thien-2-ylcarbonylaminomethyl, pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C2H4CONHCH2, 3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH2CH3)CONHCH2, 1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl, 3-(benzyloxycarbonylamino)propyl, 2-[(diphenyl)methylaminocarbonyl]ethyl, 2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C6H5)CHCH3NHCO]ethyl.
(ii) Within this more preferred group (I)(a) , another even more preferred group of compounds is that wherein:
R4 and R6 are hydrogen;
R3 and R7 are, independently of each other, alkyl, or halo; and
R5 is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, or alkylsulfonyl.
Within these preferred, more preferred, and even more preferred groups of compounds, a particularly preferred group of compounds is that wherein:
Ar1 is a heteroaryl ring, preferably optionally substituted indolyl or imidazolyl, more preferably indol-5-yl, 1-methylindol-5-yl, 3-acetylindol-5-yl, 3-propionylindol-5-yl, 3-(2-methylpropionyl)indol-5-yl, imidazol-5-yl, 2-methylbenzimidazol-5-yl, or benzimidazol-5-yl;
R3 is alkyl, preferably methyl;
R5 is alkyl, alkoxy, or halo, preferably methyl, methoxy, chloro, or bromo; and
R7 is alkyl or halo, preferably methyl, chloro, or bromo.
Within these preferred, more preferred, and particularly preferred group of compounds, an even more particularly preferred group of compounds is that wherein:
R1 is alkyl, aralkyl, heteroalkyl, or -(alkylene)-C(O)xe2x80x94X where X is alkyl, amino, monosubstituted amino, disubstituted amino, or heterocyclyl,
more preferably 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl, or -(alkylene)-C(O)xe2x80x94X where X is 2- or 4-pyridylmethylamino, 1-alkoxycarbonylpyridin-4-ylamino, optionally substituted benzylamino, 4-optionally substituted benzyloxycarbonylpiperazin-1-yl, 4-optionally substituted phenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or 4-optionally substituted heteroarylpiperazin-1-yl,
most preferably 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl, 2-(2- or 4-pyridylmethylaminocarbonyl)ethyl, 2-(1-ethoxycarbonylpyridin-4-ylaminocarbonyl)ethyl, 2-(benzylaminocarbonyl)ethyl, 2-(4-benzyloxycarbonylpiperizin-1-ylcarbonyl)ethyl, 2-(4-phenylpiperazin-1-ylcarbonyl)ethyl, 2-(4-methoxycarbonylpiperazin-1-ylcarbonyl)ethyl, 2-(4-acetylpiperazin-1-yl-carbonyl)ethyl, or 2-(4-pyridin-2-ylpiperazin-1-ylcarbonyl)ethyl.
Within these preferred, more preferred, and particularly preferred groups of compounds, an alternative even more particularly preferred group of compounds is that wherein:
R1 is heteroalkyl or -(alkylene)-C(O)xe2x80x94X where X is alkyl, amino, monosubstituted amino, disubstituted amino, or heterocyclyl,
more preferably, methylsulfonylaminomethyl, phenylsulfonylaminomethyl, (3-nitrophenyl)CH2SO2NHCH2, methylcarbonylaminomethyl, 4-(methoxycarbonyl)phenylcarbonylaminomethyl, 2-(pyrrol-1-yl)phenylcarbonylaminomethyl, 3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl, phenylcarbonylaminomethyl, (C6H5)CHCH3NHCO(C2H4)CONHCH2, (4-methoxyphenyl)COC2H4CONHCH2, 4-chlorophenylsulfonylaminocarbonylaminomethyl, 5-(acetyl)thien-2-ylcarbonylaminomethyl, pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C2H4CONHCH2, 3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH2CH3)CONHCH2, 1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl, 3-(benzyloxycarbonylamino)propyl, 2-[(diphenyl)methylaminocarbonyl]ethyl, 2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C6H5)CHCH3NHCO]ethyl.
(b) Within this preferred group (I), another more preferred group of compounds is that wherein:
Ar1 is aryl and Ar2 is a phenyl ring of formula (a).
(i) Within this more preferred group (I)(b), an even more preferred group of compounds is that wherein:
R3 and R7 are, independently of each other, alkyl, alkylthio, or halo;
R4 is hydrogen, alkyl, or halo;
R5 is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, or alkylsulfonyl; and
R6 is hydrogen.
Within these preferred, more preferred and even more preferred groups of compounds, a particularly preferred group of compounds is that wherein:
Ar1 is a phenyl ring substituted with one or two substituents selected from hydroxy, methylenedioxy, or methoxycarbonyl, more preferably, 3,4-methylenedioxyphenyl, 3,4-dihydroxyphenyl, or 4-methoxycarbonylphenyl;
R3 and R7 are, independently of each other, alkyl or halo, more preferably methyl, chloro, or bromo;
R4 is alkyl, preferably methyl; and
R5 is alkyl, alkoxy, or halo, preferably methyl, methoxy, chloro, or bromo.
Within these preferred, more preferred, and particularly preferred group of compounds, an even more particularly preferred group of compounds is that wherein:
R1 is alkyl, aralkyl, heteroalkyl, or -(alkylene)-C(O)xe2x80x94X where X is alkyl, amino, monosubstituted amino, disubstituted amino, or heterocyclyl,
more preferably 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl, or -(alkylene)-C(O)xe2x80x94X where X is 2- or 4-pyridylmethylamino, 1-alkoxycarbonylpyridin-4-ylamino, optionally substituted benzylamino, 4-optionally substituted benzyloxycarbonylpiperazin-1-yl, 4-optionally substituted phenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or 4-optionally substituted heteroarylpiperazin-1-yl,
most preferably 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl, 2-(2- or 4-pyridylmethylaminocarbonyl)ethyl, 2-(1-ethoxycarbonylpyridin-4-ylaminocarbonyl)ethyl, 2-(benzylaminocarbonyl)ethyl, 2-(4-benzyloxycarbonylpiperazin-1-ylcarbonyl)ethyl, 2-(4-phenylpiperazin-1-ylcarbonyl)ethyl, 2-(4-methoxycarbonylpiperazin-1-ylcarbonyl)ethyl, 2-(4-acetylpiperazin-1-yl-carbonyl)ethyl, or 2-(4-pyridin-2-ylpiperazin-1-ylcarbonyl)ethyl.
Within these preferred, more preferred, and particularly preferred groups of compounds, an alternative even more particularly preferred group of compounds is that wherein:
R1 is heteroalkyl or -(alkylene)-C(O)xe2x80x94X where X is alkyl, amino, monosubstituted amino, disubstituted amino, or heterocyclyl,
more preferably, methylsulfonylaminomethyl, phenylsulfonylaminomethyl, (3-nitrophenyl)CH2SO2NHCH2, methylcarbonylaminomethyl, 4-(methoxycarbonyl)phenylcarbonylaminomethyl, 2-(pyrrol-1-yl)phenylcarbonylaminomethyl, 3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl, phenylcarbonylaminomethyl, (C6H5)CHCH3NHCO(C2H4)CONHCH2, (4-methoxyphenyl)COC2H4CONHCH2, 4-chlorophenylsulfonylaminocarbonylaminomethyl, 5-(acetyl)thien-2-ylcarbonylaminomethyl, pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C2H4CONHCH2, 3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH2CH3)CONHCH2, 1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl, 3-(benzyloxycarbonylamino)propyl, 2-[(diphenyl)methylaminocarbonyl]ethyl, 2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C6H5)CHCH3NHCO]ethyl.
(ii) Another even more preferred group of compounds in group (I)(b), is that wherein:
R4 and R6 are hydrogen;
R3 and R7 are, independently of each other, alkyl, or halo; and
R5 is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, or alkylsulfonyl.
Within these preferred, more preferred and even more preferred groups of compounds, a particularly preferred group of compounds is that wherein:
Ar1 is a phenyl ring substituted with one or two substituents selected from hydroxy, methylenedioxy, or methoxycarbonyl, more preferably, 3,4-methylenedioxyphenyl, 3,4-dihydroxyphenyl, or 4-methoxycarbonylphenyl;
R3 is alkyl, preferably methyl;
R5 is alkyl, alkoxy, or halo, preferably methyl, methoxy, chloro, or bromo; and
R7 is alkyl or halo, preferably methyl, chloro, or bromo.
Within these preferred, more preferred, and particularly preferred group of compounds, an even more particularly preferred group of compounds is that wherein:
R1 is alkyl, hydroxyalkyl, aralkyl, heteroalkyl, or -(alkylene)-C(O)xe2x80x94X where X is alkyl, amino, monosubstituted amino, disubstituted amino, or heterocyclyl,
more preferably 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl, or -(alkylene)-C(O)xe2x80x94X where X is 2- or 4-pyridylmethylamino, 1-alkoxycarbonylpyridin-4-ylamino, optionally substituted benzylamino, N-(optionally substituted carbonyl)methylamino, N-(optionally substituted amido)methylamino, 4-optionally substituted benzyloxycarbonylpiperazin-1-yl, 4-optionally substituted phenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or 4-optionally substituted heteroarylpiperazin-1-yl, 4-methanesulfonyl-piperazin-1-yl, 4-acetylpiperazin-1-yl, 4-optionally substituted phenoxypiperazin-1-yl, most preferably 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl, 2-(2- or 4-pyridylmethylamino-carbonyl)ethyl, 2-(1-ethoxycarbonylpyridin-4-ylaminocarbonyl)-ethyl, 2-(benzylaminocarbonyl)ethyl, 2-(4-benzyloxycarbonylpiperazin-1-ylcarbonyl)-ethyl, 2-(4-phenylpiperazin-1-ylcarbonyl)ethyl, 2-(4-methoxycarbonylpiperazin-1-ylcarbonyl)ethyl, 2-(4-acetylpiperazin-1-ylcarbonyl)ethyl, or 2-(4-pyridin-2-ylpiperazin-1-ylcarbonyl)ethyl.
Within these preferred, more preferred, and particularly preferred groups of compounds, an alternative even more particularly preferred group of compounds is that wherein:
R1 is heteroalkyl or -(alkylene)-C(O)xe2x80x94X where X is alkyl, amino, monosubstituted amino, disubstituted amino, or heterocyclyl,
more preferably, methylsulfonylaminomethyl, phenylsulfonylaminomethyl, (3-nitrophenyl)CH2SO2NHCH2, methylcarbonylaminomethyl, 4-(methoxycarbonyl)phenylcarbonylaminomethyl, 2-(pyrrol-1-yl)phenylcarbonylaminomethyl, 3-cyanophenylaminocarbonylaminomethyl, thien-2-ylphenylcarbonylaminomethyl, phenylcarbonylaminomethyl, (C6H5)CHCH3NHCO(C2H4)CONHCH2, (4-methoxyphenyl)COC2H4CONHCH2, 4-chlorophenylsulfonylaminocarbonylaminomethyl, 5-(acetyl)thien-2-ylcarbonylaminomethyl, pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C2H4CONHCH2, 3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH2CH3)CONHCH2, 1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl, 3-(benzyloxycarbonylamino)propyl, 2-[(diphenyl)methylaminocarbonyl]ethyl, 2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C6H5)CHCH3NHCO]ethyl.
II. Another preferred group of compounds is that wherein:
R is xe2x80x94CH(R2)Ar1 wherein R2 is alkyl.
Within this group (II), a more preferred group of compounds is that wherein:
(a) Ar1 is a heteroaryl ring, preferably optionally substituted indolyl or imidazolyl, more preferably indol-5-yl, 1-methylindol-5-yl, 3-acetylindol-5-yl, 3-propionylindol-5-yl, 3-(2-methylpropionyl)indol-5-yl, imidazol-5-yl, 2-methylbenzimidazol-5-yl, benzimidazol-5-yl; and
Ar2 is a phenyl ring of formula (a).
Another more preferred group of compounds is that wherein:
(b) Ar1 is aryl, preferably a phenyl ring substituted with one or two substituents selected from hydroxy, methylenedioxy, or methoxycarbonyl, more preferably, 3,4-methylenedioxyphenyl, 3,4-dihydroxyphenyl, or 4-methoxycarbonylphenyl; and
Ar2 is a phenyl ring of formula (a).
Within the more preferred groups II(a) and (b), an even more preferred group of compounds is that wherein:
(i) R3 and R7 are, independently of each other, hydrogen, alkyl, alkylthio, or halo, preferably methyl, methylthio, chloro, or bromo, more preferably methyl, chloro, or bromo;
R4 is hydrogen, alkyl or halo, preferably methyl, chloro, or bromo;
R5 is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, or alkylsulfonyl, preferably alkyl, alkoxy, or halo, more preferably methyl, methoxy, chloro, or bromo; and
R6 is hydrogen.
(ii) Another even more preferred group of compounds within groups II(a) and (b) is that wherein:
R3 and R6 are hydrogen;
R4 and R7 are, independently of each other, alkyl, or halo, preferably methyl, chloro, or bromo; and
R5 is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, or alkylsulfonyl, preferably alkyl, alkoxy, or halo, more preferably methyl, methoxy, chloro, or bromo.
(iii) Another even more preferred group of compounds within groups II(a) and (b) is that wherein:
R4 and R6 are hydrogen
R3 and R7 are, independently of each other, alkyl, or halo; and
R5 is alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, or alkylsulfonyl.
Within the above preferred, more preferred and an even more preferred groups of (II)a and (II)b, a particularly preferred group of compounds is that wherein:
R1 is alkyl, aralkyl, heteroalkyl, or -(alkylene)-C(O)xe2x80x94X where X is alkyl, amino, monosubstituted amino, disubstituted amino, or heterocyclyl,
more preferably 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl, or -(alkylene)-C(O)xe2x80x94X where X is 2- or 4-pyridylmethylamino, 1-alkoxycarbonylpyridin-4-ylamino, optionally substituted benzylamino, 4-optionally substituted benzyloxycarbonylpiperazin-1-yl, 4-optionally substituted phenylpiperazin-1-yl, 4-alkoxycarbonylpiperazin-1-yl, or 4-optionally substituted heteroarylpiperazin-1-yl,
most preferably 2-propyl, hydroxymethyl, tert-butoxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-amidopropyl, acetyloxymethyl, benzyl, methoxymethyl, 2-(2- or 4-pyridylmethylaminocarbonyl)ethyl, 2-(1-ethoxycarbonylpyridin-4-ylaminocarbonyl)ethyl, 2-(benzylaminocarbonyl)ethyl, 2-(4-benzyloxycarbonylpiperizin-1-ylcarbonyl)ethyl, 2-(4-phenylpiperazin-1-ylcarbonyl)ethyl, 2-(4-methoxycarbonylpiperazin-1-ylcarbonyl)ethyl, 2-(4-acetylpiperazin-1-yl-carbonyl)ethyl, or 2-(4-pyridin-2-ylpiperazin-1-ylcarbonyl)ethyl.
Within the above preferred, more preferred and even more preferred groups of (II), an alternative particularly preferred group of compounds is that wherein:
R1 is heteroalkyl or -(alkylene)-C(O)xe2x80x94X where X is alkyl, amino, monosubstituted amino, disubstituted amino, or heterocyclyl,
more preferably, methylsulfonylaminomethyl, phenylsulfonylaminomethyl, (3-nitrophenyl)CH2SO2NHCH2, methylcarbonylaminomethyl, 4-(methoxycarbonyl)phenylcarbonylaminomethyl, 2-(pyrrol-1-yl)phenylcarbonylaminomethyl, 3-cyanophenylaminocarbonylaminomethyl, thien-2-ylcarbonylaminomethyl, phenylcarbonylaminomethyl, (C6H5)CHCH3NHCO(C2H4)CONHCH2, (4-methoxyphenyl)COC2H4CONHCH2, 4-chlorophenylsulfonylaminocarbonylaminomethyl, 5-(acetyl)thien-2-ylcarbonylaminomethyl, pyridin-3-ylcarbonylaminomethyl, (3,4,5-trimethoxyphenyl)C2H4CONHCH2, 3-methoxyphenylaminocarbonylaminomethyl, (phenoxy)CH(CH2CH3)CONHCH2, 1-(ethoxycarbonyl)piperidin-4-yl-aminomethylcarbonylaminomethyl, 3-(benzyloxycarbonylamino)propyl, 2-[(diphenyl)methylaminocarbonyl]ethyl, 2-[2-(methyl)butylaminocarbonyl]ethyl, or 2-[(C6H5)CHCH3NHCO]ethyl.
III. A third preferred group of compounds is that wherein:
R is xe2x80x94CH(R2)Ar1 wherein R2 is hydrogen;
Ar1 is heteroaryl; and
Ar2 is a naphthyl ring of formula (b).
IV. A fourth preferred group of compounds is that wherein:
R is xe2x80x94CH(R2)Ar1 wherein R2 is hydrogen;
Ar1 is aryl; and
Ar2 is a naphthyl ring of formula (b).
V. A fifth preferred group of compounds is that wherein:
R is xe2x80x94CH(R2)CHxe2x95x90CHAr1 wherein R2 is hydrogen;
Ar1 is heteroaryl; and
Ar2 is a phenyl ring of formula (a) or a naphthyl ring of formula (b).
IV. A sixth preferred group of compounds is that wherein:
R is xe2x80x94CH(R2)CHxe2x95x90CHAr2 wherein R2is hydrogen;
Ar1 is aryl; and
Ar2 is a phenyl ring of formula (a) or a naphthyl ring of formula (b).
Within the broadest definition of this invention set forth in the Summary of the Invention, certain compounds of Formula (I) wherein Z is xe2x80x94OH are preferred as intermediates in the synthesis of compounds wherein Z is xe2x80x94NHOH.
Compounds of this invention can be made by the methods depicted in the reaction schemes shown below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemie, or Sigma (St. Louis, Mo., USA), Calbiochem-Novabiochem (San Diego, Calif.) or Indofine Chemical Co. (Bellemead, N.J., USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd""s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March""s Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
Schemes A, B, and C describe alternative methods to generate the compounds of Formulae (Ia) and (Ib).
A compound of Formula (Ia) or (Ib) wherein R is xe2x80x94CH(R2)Ar1 , R1, and Ar2 are as defined in the Summary of the Invention is prepared from a suitably N-protected xcex1-amino 1 as shown in Scheme A. 
Treatment of an xcex1-aminoacetate of formula 1 (where R is an alkyl such as methyl, ethyl, or tert-butyl or an aralkyl such as benzyl) with a compound of formula 2 where R2 is hydrogen or alkyl under reductive amination reaction conditions i.e., in the presence of a suitable reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, and the like) and an organic acid (e.g., glacial acetic acid, trifluoroacetic acid, and the like) provides an N-alkylated xcex1-amino ester of formula 3. Suitable solvents for the reaction are halogenated hydrocarbons (e.g., 1,2-dichloroethane, chloroform, and the like).
Compounds of formula 1 are commercially available or they can be prepared by methods well known in the art. For example, esters of natural and unnatural amino acids such as D-valine benzyl ester p-tosylate salt, D-valine ethyl ester hydrochloride salt, D-valine tert-butyl ester hydrochloride salt, L-, D- or DL-serine methyl ester are commercially available. Alpha-thiomethyl amino acids can be prepared by following the procedures described in Arnold, L. D., Kalantar, T. H., Vederas, J. C. J. Am. Chem. Soc., 107, 7108, (1985). Others can be prepared by esterification of N-protected xcex1-amino acids (suitable amino-protecting group are tert-butoxycarbonyl, benzyloxycarbonyl, and the like), followed by deprotection of the amino group as described in Example 1.
Sulfonylation of 3 with an arylsulfonyl chloride of formula 4 provides a 2-(arylsulfonylamino)acetate of formula 5. The sulfonylation reaction can be carried out by methods well known in the art e.g., reacting 3 with a compound of formula 4 in the presence of trimethylsilylcyanide in acetonitrile. Compounds of formula 4 are commercially available or they can be prepared by methods well known in the art. For example, 4-methoxy-benzenesulfonyl chloride, 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride, 4-chloro-2,5-dimethylbenzenesulfonyl chloride, 2-dibenzofuransulfonyl chloride, 4-bromobenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, and 1-naphthalenesulfonyl chloride are commercially available. Others can be prepared by the procedures described in Bosshard, E. H. et. al., Helv. Chim. Acta, 42, 1653, (1959); Colter, A. K. and Turkos, R. E. C., Canadian J. of Chem., 56, 585, (1978); Buchanan, G. W.,et. al., J. Org. Chem, 40, 2357-2359 (1975) and Fujino, M, et. al., Chem. Pharm. Bull. 10, 2825-2831 (1981). Typically, an unsulfonylated arene is treated with chlorosulfonic acid in dichloromethane at xe2x88x925xc2x0 C. to 10xc2x0 C. to give the desired arenesulfonyl chloride.
Conversion of 5 to the corresponding carboxylic acid is dependent on the nature of the R group. For example, if R is a benzyl group then it is removed under hydrogenation reaction conditions. If R is an alkyl group such as methyl or ethyl group then it is removed under basic hydrolysis reaction conditions i.e., in the presence of an aqueous base (e.g., sodium hydroxide, lithium hydroxide, and the like) in an alcoholic organic solvent such as methanol, ethanol, and the like. If R is the tert-butyl group, then it is removed under acidic conditions. 
Compound 6 can be converted to a compound of Formula (Ia) or (Ib) by converting 6 to an acyl derivative of formula 7 where Y is a leaving group under acylating conditions (e.g., chloro, succinimido, and the like). Treatment of 7 with N,O-bis-trimethylsilylhydroxylamine followed by acidic workup or upon the addition of methanol provides a compound of Formula (Ia) or (Ib) directly. 
The acyl derivative 7 can be prepared by methods known to those of ordinary skill in the art. For example, compound 7 where Y is chloro can be prepared by reacting compound 5 with a chlorinating agent such as oxalyl chloride in a suitable organic solvent such as methylene chloride. 
Alternatively, a compound of Formula (Ia) or (Ib) can be prepared from a compound of formula 6 via two steps by first reacting 6 with an O-substituted hydroxylamine (e.g., O-benzylhydroxylamine, O-tert-butylhydroxylamine, and the like) to give an O-protected hydroxamate of formula 8. The reaction is carried out in the presence of a coupling agent (e.g., N,N-dicyclohexylcarbodiimide, N-ethyl-Nxe2x80x2-(3-dimethylamino-propyl)carbodiimide, and the like), an organic base (e.g., dimethylamino-pyridine, triethylamine, pyridine, N-methylmorpholine, and the like) and optionally hydroxybenzotriazole. Suitable solvents for the reaction are methylene chloride, dichloroethane, dimethylformamide, and the like. Removal of the O-protecting group then provides a compound of Formula (Ia) or (Ib). The reaction conditions utilized depend on the nature of the Rxe2x80x2 group e.g., if Rxe2x80x2 is tert-butyl, then the reaction is carried out in an inert solvent such as dichloromethane, in the presence of an acid (e.g., dry hydrogen chloride, trifluoroacetic acid, and the like). If Rxe2x80x2 is benzyl, then hydrogenolysis conditions utilizing a metal catalyst such as palladium in an inert solvent such as ethyl acetate or tetrahydrofuran are required. A compound of formula 5, 7, or 8 can also be converted to a compound of Formula (Ia) or (Ib) by the procedures described in PCT Application, Publication No. 98/32748.
A compound of Formula (Ia) or (Ib) where R is xe2x80x94CH(R2)Ar1 and other groups are as defined in the Summary of the Invention can also be prepared from an xcex1-amino acetate 1 as shown in Scheme B. 
Sulfonylation of a compound of formula 1 with an arylsulfonyl chloride under the reaction conditions described in Scheme A above, provides 2-arylsulfonylacetate of formula 9 which is converted to a compound of formula 5 either: 
(a) by reacting compound 9 where with an alkylating agent of formula Ar1CHR2X (where X is a leaving group such as chloro, bromo, mesylate, triflate, and the like under alkylating conditions) in the presence of a base (e.g., sodium carbonate, potassium carbonate, cesium carbonate, and the like) and in a suitable solvents such as tetrahydrofuran, dioxane, N,N-dimethylformamide and the like; or
(b) by reacting compound 9 with an alcohol of formula Ar1CHR2OH in the presence of a trialkylphosphine or a triaryl phosphine, preferably tributylphosphine, triphenylphosphine, preferably tributylphosphine, and a dialkyl azodicarboxylate such as diethyl or diisopropyl azodicarboxylate or (1,1xe2x80x2-azodicarbonyl)dipiperidine, preferably (1,1xe2x80x2-azo-dicarbonyl)dipiperidine. Suitable solvents include aromatic hydrocarbons such as benzene, and the like.
Compound 5 is then converted to a compound of Formula (Ia) or (Ib) as described in Scheme A above. 
A compound of Formula (Ia) or (Ib) where R is xe2x80x94CH(R2)Ar1 and other groups are as defined in the Summary of the Invention can also be prepared from an xcex1-aminoacid 11 as shown in Scheme C. 
Sulfonylation of an xcex1-amino acid 11 with an arylsulfonyl chloride of formula 4 in the presence of a base such as triethylamine provide 2-arylsulfonylamino acetic acid of formula 12. The reaction is carried out in an organic solvent and water mixture such as tetrahydrofuran and water. Compound 12 can be converted to a compound of Formula (Ia) or (Ib) by method (a) or (b). 
In method (a), esterification of 12 provides a compound of formula 9 (where R is alkyl such as methyl, tert-butyl or aralkyl such as benzyl) which is then converted to a compound of Formula (Ia) or (Ib) by proceeding as described in Schemes A and B above. 
In method (b), compound 12 is reacted with an N,O-protected hydroxylamine, such as O-(2,4dimethoxy-benzyl)-N-(2,4,6-trimethoxybenzyl)hydroxylamine, under the conditions described in Barlaam, B., et al., Tet. Lett., Vol. 39, 7865, (1998) to give a compound of formula 13. Alkylation of 13 provides a compound of formula 14 which upon treatment with trifluoroacetic acid in methylene chloride in the presence of triethylsilane provides a compound of Formula (Ia) or (Ib) ((see., Barlaam, B., et al., Tet. Lett., Vol. 39, 7865, (1998)).
A compound of Formula (Ia) or (Ib) where R is xe2x80x94CH(R2)CHxe2x95x90CHAr1 and other groups are as defined in the Summary of the Invention can also be prepared from an xcex1-amino acetate 1 as shown in Scheme D. 
A compound of Formula (Ia) or (Ib) were R is xe2x80x94CH(R2)CHxe2x95x90CHAr1 is prepared by alkylating a compound of formula 9 (R cannot be benzyl) with an alkylating agent of formula 15 where X is a leaving group under alkylating conditions (e.g., chloro, bromo, mesylate, triflate, and the like) in the presence of a base (e.g., sodium carbonate, potassium carbonate, cesium carbonate, and the like) and in a suitable solvents such as tetrahydrofuran, dioxane, N,N-dimethylformamide and the like, to give a compound of formula 16. Hydrolysis of the ester group in 16 gives the corresponding acid which is then converted to a compound of Formula (Ia) or (Ib) by preparing the acid chloride derivative followed by treatment with N,O-bis-trimethylsilylhydroxylamine as described in Scheme A above. 
A compound of formula 15 such as cinnamyl chloride is commercially available. 
A compound of Formula (Ia) or (Ib) wherein Ar2 is as defined in the Summary of the Invention, R is CH2Ar1 (wherein Ar1 is 3,4-methylenedioxyphenyl), and R1 is xe2x80x94CH2NHCOORxe2x80x3 (wherein Rxe2x80x3 is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclylalkyl) can be prepared from N-protected diaminopropionic acid 2, as shown in Scheme E and as described more fully in Example 16. 
A compound of Formula (Ia) or (Ib) wherein Ar2 is as defined in the Summary of the Invention, R is CH2Ar1 (wherein Ar1 is 3,4-methylenedioxyphenyl), and R1 is xe2x80x94CH2NHCONHAr can be prepared from the resin of formula 7 (of Scheme E) as shown in Scheme F and as described more fully in Example 17. 
Compounds of this invention are useful in the treatment of diseases associated with excessive deposition of interstitial collagens, exemplified by interstitial pulmonary fibrosis, pericentral fibrosis, Symmers"" fibrosis, perimuscular fibrosis, kidney and liver fibrosis, idiopathic pulmonary fibrosis, endocardial sclerosis, hepatitis, acute respiratory distress syndrome, arthritis, cystic fibrosis, tendon surgery, surgical adhesions, corneal scarring, and restenosis.
Compounds of this invention are inhibitors of procollagen C-proteinase. Therefore, they inhibit C-terminal processing of types I, II, and III collagens necessary for their ability to form insoluble collagen fibrils. Furthermore, selected compounds of the invention selectively inhibit procollagen C-proteinase over other collagen degradating enzymes such as collagenase-1, collagenase-2, and collagenase-3. Therefore, the natural resorption of collagen mediated by collagenase-1, collagenase-2 and collagenase-3 is largely unaffected resulting in compounds of greater therapeutic efficacy. In particular, preferred compounds of this invention inhibit procollagen C-proteinase with greater than 100 fold selectivity over collagenase-1, collagenase-2, and collagenase-3. Selective inhibition of procollagen C-proteinase over collagenase-1, collagenase-2, and collagenase-3 was demonstrated by the assays described in the Examples. Thereby, this invention allows the treatment of fibrotic diseases by administering to a patient an agent that selectively inhibits procollagen C-proteinase over collagenase-1 collagenase-2, and collagenase-3.
The ability of the compounds of Formulae (Ia) and (Ib) to inhibit procollagen C-proteinase activity, may be demonstrated by a variety of in vitro assays known to those of ordinary skill in the art, such as the assay described in Example 21. The selectivity against collagenase enzymes may be determined by the assay described in Example 22.
The in vivo efficacy of compounds of Formulae (Ia) and (Ib) against fibrotic disease and the deposition of collagen may be shown by numerous animal models including the mouse bleomycin induced pulmonary fibrosis model ((Phan, S. H., et.al. xe2x80x9cBleomycin-induced Pulmonary Fibrosis,xe2x80x9d Am. Rev. Respir. Dis., 124:428-434 (1981) and Piguet, P. F., et al. xe2x80x9cEffective Treatment of the Pulmonary Fibrosis Elicited in Mice by Bleomycin or Silica with anti-CD-11 Antibodies,xe2x80x9d Am. Rev. Resp. Dis., 147:435-441 (1993)), the sponge implant model ((Unemori, E. N., et al. xe2x80x9cHuman Relaxin Decreases Collagen Accumulation In Vivo in Two Rodent Models of Fibrosis,xe2x80x9d J. Invest. Dermatol., 101:280-285 (1993)), the carbon tetrachloride or NDMU induced renal fibrosis model, as well as other animal models cited in WO 97/05865 (xe2x80x9cC-Proteinase Inhibitors for the Treatment of Disorders Relating to the Overproduction of Collagenxe2x80x9d), published Feb. 20, 1997.
In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors. The drug can be administered more than once a day, preferably once or twice a day.
Therapeutically effective amounts of compounds of Formula (Ia) or (Ib) may range from approximately 0.05-50 mg per kilogram body weight of the recipient per day; preferably about 0.3-20 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 21 mg to 1.4 g per day.
In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is systemic using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
Intranasal delivery is typically accomplished with dry powder formulations, liquid solutions or suspensions suitable for nebulization or with aerosol propellants suitable for use in a metered dose inhaler. Alternatively, drug substance may be associated with microspheres made of materials such as gelatin, dextran, collagen or albumin The microspheres are conveniently delivered in freeze dried form with a nasal insufflator device or a pressurized aerosol cannister. Penetration enhancers such as amphiphilic steroids may also be used as additives to increase the systemic absorption of the drug into the tissue.
Effective administration may also be accomplished by pulmonary or respiratory delivery since polypeptides are readily absorbed through the cellular lining of the alveolar region of the mammalian lung. Advantageously, such administration frequently does not require the use of penetration enhancers as additives. Devices and methods for pulmonary delivery deep into the lung are described in U.S. Pat. No. 5,780,014, issued Jul. 14, 1998 and U.S. Pat. No. 5,814,607, issued Sep. 29, 1998.
Lastly, compounds may be systemically administered by transdermal delivery, which typically involves placing the drug on the surface of the skin and allowing it to permeate through the skin. Transdermal delivery devices employ a structure such as an adhesive patch or the like that serves as a reservoir for the drug and brings the drug into diffusive contact with the skin. In one general typ, the structure is a three dimensionally stable matrix known as a monolithic matrix. Such matrices are described in more detail in U.S. Pat. Nos. 5,804,214, 5,149,538 and 4,956,171 which describe matrices made of polymers and copolymers of acrylic latexes, acrylic esters, methacrylic esters and vinyl acetates.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of in general, a compound of Formula (Ia) or (Ib) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (Ia) or (Ib). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their formulations are described in Remington""s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of formula I based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula (Ia) or (Ib) are described in Example 18.